US7321044B2ExpiredUtilityPatentIndex 55
Synthesis of oxygen-substituted benzocycloheptenes as valuable intermediate products for the production of tissue-selective estrogens
Est. expiryOct 12, 2021(expired)· nominal 20-yr term from priority
Inventors:PLATZEK JOHANNESBECKMANN WOLFGANGGEISLER JENSKIRSTEIN HOLGERNIEDBALLA ULRICHOTTOW ECKHARDRADAU SIGMARSCHULZ CLAUDIAWESSA THOMAS
C07D 333/22C07C 309/65C07C 45/46C07C 2602/12C07C 67/03C07D 213/50C07C 59/64C07C 43/225C07D 213/30C07C 51/367C07C 49/755C07C 315/02C07C 69/738A61P 5/30C07C 69/736C07C 303/28C07D 333/16C07D 333/24C07C 303/26C07D 213/55C07D 213/16C07C 51/36
55
PatentIndex Score
2
Cited by
30
References
34
Claims
Abstract
The invention relates to intermediate products and a new process for the production of benzocycloheptene C. The process for the production of its new intermediate products according to the invention starts from economical starting materials, provides the intermediate stages in high yields and high purity, without chromatographic purification steps, and allows production on an industrial scale.
Claims
exact text as granted — not AI-modified1. A process for the production of compounds of formula I
in which
L is a C 2 –C 10 alkylene chain, which can be unbranched or branched,
X is Cl or Br,
Ar is an aromatic or heteroaromatic radical, which optionally can be substituted with up to 3 substituents,
said process comprising:
cleaving the aromatic methyl ether in a compound of formula II
with a reagent comprising boron tribromide and 2,6-dimethylpyridine.
2. A process for the production of compounds of formula II
in which
L is a C 2 –C 10 alkylene chain, which can be unbranched or branched,
X is Cl or Br,
Ar is an aromatic or heteroaromatic radical, which optionally can be substituted with up to 3 substituents,
said process comprising:
reacting a compound of formula III
in which
Ar is an aromatic or heteroaromatic radical, which optionally can be substituted with up to 3 substituents,
R is a perfluorinated, straight-chain C 1 –C 8 alkyl group, with a compound of formula IV
in which
L is a C 2 –C 10 alkylene chain, which can be unbranched or branched,
X is Cl or Br,
under palladium catalysis.
3. A process for the production of compounds of formula III
in which
Ar is an aromatic or heteroaromatic radical, which optionally can be substituted with up to 3 substituents,
R is a perfluorinated, straight-chain C 1 –C 8 alkyl group,
said process comprising:
reacting a compound of formula V
with a compound of formula VI
R—SO 2 Nu (VI)
in which
R is a perfluorinated, straight-chain C 1 –C 8 alkyl group,
Nu is a leaving group,
in the presence of an organic or inorganic base in an aprotic solvent.
4. A process for the production of compounds of formula IX
in which
Ar is an aromatic or heteroaromatic radical, which optionally can be substituted with up to 3 substituents,
said process comprising:
reacting 3-methoxybenzaldehyde and acetaldehyde under base catalysis to produce 3-methoxycinnamaldehyde which is then reacted in a subsequent Knoevenagel condensation with an arylacetic acid of formula X
5. A process according to claim 1 , wherein Ar is one of the following radicals:
6. A process according to claim 5 , wherein Ar a phenyl radical, pyridyl radical or thiophene radical.
7. A compound of formula III
in which
Ar is an aromatic or heteroaromatic radical, which optionally can be substituted with up to 3 substituents, and
R is a perfluorinated C 1 –C 8 alkyl group.
8. A process comprising:
reacting 3-methoxybenzaldehyde and acetaldehyde under base catalysis to produce 3-methoxycinnamaldehyde which is then reacted in a subsequent Knoevenagel condensation with an arylacetic acids of formula X
whereby a compound of formula IX is produced,
in which
Ar is an aromatic or heteroaromatic radical, which optionally can be substituted with up to 3 substituents;
hydrogenating said compound of formula IX to obtain a compound of formula VIII
cyclizing the compound of formula VIII with polyphosphoric acid to obtain a compound of formula V
reacting under palladium catalysis the compound of formula V with a compound of formula VI
R—SO 2 Nu (VI)
in which
R is a perfluorinated, straight-chain C 1 –C 8 -alkyl group,
Nu is a leaving group,
in the presence of an organic or inorganic base in an aprotic solvent to obtain a compound of formula III
reacting the compound of formula III with a compound of formula IV
in which
L is a C 2 –C 10 alkylene chain, which can be unbranched or branched,
X is Cl or Br,
to obtain a compound of formula II
9. A process according to claim 8 , wherein, in formula II, L-X is 5-chloropentyl and Ar is phenyl, said process further comprising:
cleaving the methyl ether of formula II using boron tribromide in 2,6-dimethylpyridine,
treating the resultant compound with sodium iodide in methyl ethyl ketone,
reacting the resultant compound with 4,4,5,5,5-pentafluoropentylthioacetate, and then treating the resultant compound with sodium periodate in the presence of dichloromethane to obtain the following compound
10. A process according to claim 2 , wherein the palladium-catalyst complex that is used contains either Pd(O) or Pd(II) in the complex.
11. The compound of the formula:
12. The compound of the formula:
13. A process for gentle and selective cleavage of aromatic methyl ethers comprising: reacting an aromatic methyl ether with a reagent comprising boron tribromide and 2,6-dimethylpyridine.
14. A process for gentle and selective cleavage of a methyl ether on an aromatic compound which further contains an ether group containing a C 2 –C 10 alkylene chain comprising: reacting the aromatic compound with a reagent-comprising boron tribromide and 2,6-dimethylpyridine.
15. A reagent consisting of boron tribromide and 2,6-dimethylpyridine.
16. A process according to claim 2 , wherein R is CF 3 , C 4 F 9 , or C 8 F 17 .
17. A process according to claim 3 , wherein R is CF 3 , C 4 F 9 , or C 8 F 17 .
18. A process according to claim 7 , wherein R is CF 3 , C 4 F 9 , or C 8 F 17 .
19. A process according to claim 3 , wherein Nu is F, Cl, I or R—SO 3 .
20. A process according to claim 9 , wherein L is a C 5 alkylene chain.
21. A process according to claim 1 , wherein said reagent contains boron tribromide and 2,6-dimethylpyridine in a ratio of 1:1 to 1:1.5.
22. A process according to claim 1 , wherein the amount of said reagent used is between 1 and 6 equivalents, relative to bromine tribromide and the aromatic methyl ether that is to be cleaved.
23. A process according to claim 1 , wherein the reaction is performed in an aprotic solvent at a temperature of −30° C. to 50° C.
24. A process according to claim 4 , wherein NaOH or KOH is used as the base for the base catalysis.
25. A process according to claim 4 , wherein the reaction takes place in water at a temperature of between 1–30° C.
26. A process according to claim 4 , wherein in the Knoevenagel condensation acetic anhydride and triethylamine are used as a base.
27. A process according to claim 1 , wherein L is —C 2 H 4 —, —C 3 H 6 —, CH 2 —CH(CH 3 )—CH 2 , —C 4 H 8 —, —C 5 H 10 —, —C 6 H 12 —, —C 7 H 14 —, or —C 8 H 16 —.
28. A process according to claim 2 , wherein L is —C 2 H 4 —, —C 3 H 6 —, CH 2 —CH(CH 3 )—CH 2 , —C 4 H 8 —, —C 5 H 10 —, —C 6 H 12 —, —C 7 H 14 —, or —C 8 H 16 —.
29. A process for the production of compounds of formula V
wherein Ar is selected from the following radicals:
said process comprising:
reacting a compound of formula VIII with polyphosphoric acid
30. A process according to claim 4 , wherein Ar is selected from the following radicals:
31. A process according to claim 4 , wherein Ar is phenyl which optionally can be substituted with up to 3 substituents, and said Knoevenagel condensation with an arylacetic acid of formula X is performed at 100° C.
32. A process according to claim 1 , wherein said reagent consists of boron tribromide and 2,6-dimethylpyridine.
33. A process according to claim 13 , wherein said reagent consists of boron tribromide and 2,6-dimethylpyridine.
34. A process according to claim 14 , wherein said reagent consists of boron tribromide and 2,6-dimethylpyridine.Cited by (0)
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